ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.912G>A (p.Gln304=) (rs199475583)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000672215 SCV001146755 likely pathogenic Phenylketonuria 2019-08-06 reviewed by expert panel curation The c.912G>A (p.Gln304Gln) variant in PAH has been reported in multiple PKU patients (BH4 deficiency excluded in some) (PMID: 23514811). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF=0.000004). This is a synonymous variant that occurs at the junction of exon8/intron8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~20%) the canonical donor site. p.Gln304= has been detected with multiple pathogenic variants without confirmation of parental testing to determine phase: R241H (VarID102804, PMID: 27413125); K363fsdelG (c.1089delG, VarID102518, PMID: 8659548); I65T (VarID636) and A300S (VarID92751, PMID: 2351481); p.R176L (VarID631, PMID: 23500595). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_strong, PP4_moderate.
Counsyl RCV000672215 SCV000797301 likely pathogenic Phenylketonuria 2018-01-22 criteria provided, single submitter clinical testing
Invitae RCV000672215 SCV000932901 pathogenic Phenylketonuria 2018-11-09 criteria provided, single submitter clinical testing This sequence change affects codon 304 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant also falls at the last nucleotide of exon 8 of the PAH coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199475583, ExAC 0.009%). This variant (also known as p.Gln304Gln) has been observed in several individuals affected with hyperphenylalaninemia (PMID: 8659548, 23500595, 24941924, 9359039). ClinVar contains an entry for this variant (Variation ID: 102892). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000672215 SCV001271163 uncertain significance Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089154 SCV000119768 not provided not provided no assertion provided not provided

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